This invention relates to the pharmaceutical and medical arts. In particular the invention pertains to beta-lipotropin, fragments and analogs thereof, pharmaceutical formulations, and methods for using same in treating diabetes and other associated conditions in mammals.
Proopiomelanocortin (POMC) is a neuropeptide precursor molecule which is translocated to secretory pathways within neuroendocrine cells. POMC is cleaved by the action of specific endopeptidases to yield peptides such as adrenocorticotrophic hormone (ACTH), Beta-lipotropin (BLT), Beta-endorphin, and Melanocyte Stimulating Hormone (MSH). The processing of POMC into one or more specific peptides occurs in a tissue and cell specific manner (See generally, M. Castro and E. Morrison, Crit. Rev. Neurobiol., 11, 35-57, 1997; Roberts, J. L. and Herbert, E., Proc Nat Acad Sci, 74, 4826 (1977); Roberts, J. L. and Herbert, E., Proc.Nat.Acad.Sci 74, 5300 (1977); Mains, et al., Proc.Nat.Acad.Sci 74, 3014 (1977)). POMC is produced mainly in the pituitary gland and hypothalamus. Post-translational processing of POMC in the anterior pituitary produces ACTH and BLT. On the other hand, the major products of the intermediate pituitary are .alpha.-MSH, CLIP, .gamma.-lipotropin, .beta.-endorphin, and .beta.-MSH, while in the hypothalamus, POMC is processed primarily into .gamma.-MSH and .beta.-endorphin.
POMC-derived peptides perform a variety of important roles in metabolic and physiological regulation. For example, ACTH, a 39 amino acid peptide, stimulates secretion of glucocorticoids from the adrenal cortex. The MSH's, on the other hand, stimulate melanin synthesis by melanocytes in the skin, and also appear to be involved in fat metabolism. .beta.-endorphin derives from the carboxyl end of BLT (viz. Residues 59 to 89 of the human sequence), and possesses analgesic activity that is antagonized by naloxone, a known antagonist for morphine. Thus, POMC-derived peptide hormones have diverse roles in physiologic and metabolic regulation.
Proper glucose and fuel metabolism depend on the non-POMC related peptide, insulin. Specifically, insulin stimulates glycogen, fatty acid, and protein synthesis, and also stimulates glycolysis. Insulin is critical in promoting entry of glucose into muscle and fat cells.
Defective insulin metabolism may lead to diabetes. Type 1 diabetics require exogenous insulin administration for proper control of fuel and glucose metabolism. On the other hand, Type 2 diabetics typically do not require exogenous insulin until the later stages of the disease. Proper control of glucose and fuel metabolism is essential for effective management of diabetes. Without this, there can be serious, perhaps even fatal, consequences including ketoacidosis, coma, retinopathy, diabetic microangiopathy, atherosclerosis, myocardial infarction, stroke, gangrene, hypertriglyceridemia, hypercholesterolemia, cardiomyopathy, dermopathy, diabetic foot syndrome, nephropathy, urinary tract infection, papillary necrosis, cataracts, diabetic gastroenteropathy, constipation, peripheral vascular disease, and even death. In many instances, a delicate balance must be struck between administration of too much insulin and too little insulin. Therefore, an ideal therapy for diabetes would be one that controls blood glucose levels by improving sensitivity to insulin.
Described herein is a method for treatment and pharmaceutical composition that is effective in treating or preventing type 1 and type 2 diabetes, and associated complications thereof, comprising the administration of a pharmaceutically effective amount of beta-lipotropin and/or fragments and/or analogs thereof.